Ruthenium-catalyzed alkylative lactonization and carbocyclization

Article abstract of DOI:10.1021/ol0610136

The cationic ruthenium complex [CpRu(NCCH₃)₃]PF ₆ promotes the coupling of monosubstituted allene carboxylic acids and simple α,β-unsaturated olefins to form five- and six-membered lactones. The mild reaction conditions al

Full text of DOI:10.1021/ol0610136

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3627-3629
Ruthenium-Catalyzed Alkylative
Lactonization and Carbocyclization
Barry M. Trost* and Andrew McClory
Department of Chemistry, Stanford UniVersity, Stanford, California 94305
bmtrost@stanford.edu
Received April 27, 2006
ABSTRACT
The cationic ruthenium complex [CpRu(NCCH3)3]PF6 promotes the coupling of monosubstituted allene carboxylic acids and simple
r,â-
unsaturated olefins to form five- and six-membered lactones. The mild reaction conditions allow for the presence of various functional groups.
The development of atom-economical reactions is one of
the most important challenges to be met in contemporary
organic synthesis.1 To the extent that we can increase
the number of addition reactions in a synthetic sequence,
we improve the efficiency with which we use our raw
materials. Thus, our group has engaged in a program of
developing ruthenium-catalyzed addition reactions in which
all of the reactant atoms are expressed in the product.2 The
development of one such reaction, ruthenium-catalyzed
alkylative lactonization, was envisioned. However, because
allyl esters are known substrates for ruthenium-catalyzed
allylic alkylation,3 the potential instability of such products
under the reaction conditions could be detrimental to such a
process.
The preparation of substrates was straightforward, with
most being accessed through a traditional malonic ester-type
synthesis (Scheme 1). For example, dimethyl propargyl
Scheme 1. Representative Substrate Synthesis
Some years ago, our group demonstrated that certain
ruthenium complexes can mediate C-C bond formation
between the central carbon of a terminal allene and the
â-carbon of an R,â-unsaturated olefin.4 Upon consideration
of possible mechanistic rationales, we reasoned that the
putative ruthenacycle would be intercepted by appropriately
situated nucleophiles, thus bypassing â-hydride elimina-
tion. Indeed, tethered alcohols and amines lead to formation
of the corresponding heterocyclic products.5 Herein, we
describe the use of carboxylic acids as nucleophiles in this
process.
malonate was alkylated with benzyl bromide. Hydrolysis and
decarbalkoxylation to the monoester,6 followed by homolo-
(3) Trost, B. M.; Fraisse, P.; Ball, Z. T. Angew. Chem., Int. Ed. 2002,
41, 1059-1061.
(4) Trost, B. M.; Pinkerton, A. B. J. Am. Chem. Soc. 1999, 121, 4068-
4069.
(5) (a) Trost, B. M.; Pinkerton, A. B. J. Am. Chem. Soc. 1999, 121,
10842-10843. (b) Trost, B. M.; Pinkerton, A. B.; Kremzow, D. J. Am.
Chem. Soc. 2000, 122, 12007-12008.
(1) (a) Trost, B. M. Science 1991, 254, 1471-1477. (b) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281.
(2) (a) Trost, B. M. Acc. Chem. Res. 2002, 35, 695-705. (b) Trost, B.
M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001, 101, 2067-2096.
10.1021/ol0610136 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/22/2006

gation of the alkyne to the allene7 and saponification,
gave the allene carboxylic acid substrate in good overall
yield.
Table 2. Scope of R,â-Unsaturated Olefins
The substrates were then subjected to the reaction condi-
tions. As seen in Table 1, the reaction was highly efficient
in forming the five-membered lactone products.
electrophile (R)
H
conditionsa
yield (%)
A
B
A
B
A
B
B
B
B
B
24, n ) 1, 63
25, n ) 2, 55
26, n ) 1, 78
27, n ) 2, 65
28, n ) 1, 75
29, n ) 2, 58
30, n ) 1, 79
31, n ) 2, 71
32, n ) 1, 58
33, n ) 2, 50
Table 1. Scope of Allene Carboxylic Acids
Me
Et
Ph
tBu
a A: 1.25 equiv of electrophile, 5% [CpRu(NCCH3)3]PF6, 5% CeCl3‚7H2O,
DMF,25°C,30min.B: 1.50equivofelectrophile,10%[CpRu(NCCH3)3]PF6,
10% CeCl3‚7H2O, DMF, 60 °C, 2 h.
In terms of carbonyl groups, aldehydes, methyl ketones,
and ethyl ketones functioned quite well at room tempera-
ture for five-membered ring formation, whereas the more
sterically demanding phenyl and tert-butyl ketones required
longer reaction times, higher temperatures, and increased
catalyst loadings. Introduction of substituents on the olefin
led to a recovered allene carboxylic acid substrate, as did
changing the electron-withdrawing group to a nitrile, ester,
or sulfone.
Interestingly, carbon nucleophiles of an acidity comparable
to carboxylic acids can be used in this reaction. Thus, a
Meldrum’s acid derivative can be used as a substrate to give
the corresponding carbocyclic product in which two carbon-
carbon bonds are created, one of them being quaternary
(Scheme 2).
a 1.25 equiv of MVK, 5% [CpRu(NCCH3)3]PF6, 5% CeCl3‚7H2O,
DMF, 25 °C, 30 min. b 1.50 equiv of MVK, 10% [CpRu(NCCH3)3]PF6,
10% CeCl3‚7H2O, DMF, 60 °C, 2 h. c Product was obtained as a 1:1 mix-
ture of diastereomers. d Product was obtained as a mixture of four
diastereomers.
Scheme 2. Carbon Nucleophile: Carbocycle Formation
The catalyst loading, temperature, and reaction time were
all lower than in the corresponding cyclizations of alco-
hols and amines. The compatibility of an olefin, which
could potentially form a ruthenacycle with the proximal
allene and the catalyst, is noteworthy. Both electron-rich and
electron-poor aromatic rings were tolerated in the reaction.
Functional groups that could coordinate to the catalyst, such
as ketone, ketal, and alcohol, did not interfere with the
reaction.
A plausible mechanism for this reaction is depicted in
Scheme 3. Coordination of the allene and the R,â-unsatu-
rated olefin to the ruthenium catalyst I provides com-
plex II. Oxidative coupling then leads to ruthenacycle III,
which is the key intermediate. The coordination of the
carbonyl with the cocatalyst CeCl3 may promote this step.
Although III is depicted as a σ-allyl complex, we do not
rule out its existence as a π-allyl structure. From this
complex, â-hydride elimination or E2 elimination could
The formation of lactones with simple R,â-unsaturated
olefins is seen in Table 2. In general, five-membered lac-
tones formed in higher yields than six-membered lactones.
(7) Crabbe, P.; Fillion, H.; Andre, D.; Luche, J.-L. Chem. Commun. 1979,
859-860.
(6) Krapcho, A. P.; Lovey, A. J. Tetrahedron Lett. 1973, 957-960.
3628
Org. Lett., Vol. 8, No. 17, 2006

Scheme 3. Mechanism of Ruthenium-Catalyzed Alkylative
Scheme 4. Limitations of Allene Substitution
Lactonization
In summary, an important extension of the ruthenium-
mediated formation of heterocycles from allenes and R,â-
unsaturated olefins has been reported. Substrates for the
reaction could be synthesized in high yield. The use of mild
reaction conditions and lower catalyst loadings and the
tolerance of several functional groups constitute important
features of this addition reaction. The extension to carbocycle
formation further suggests the likelihood of this process
having a broad scope in terms of the nature of the nucleophile
in the cyclization event.
eventually lead to the 1,3-diene product IV. Alternatively,
nucleophilic trapping by the tethered carboxylic acid may
give V which, following protonation of the metal and
reductive elimination, gives lactone product VI and regener-
ates the catalyst.
The tetrasubstituted allene carboxylic acid 36 did not
participate in the reaction (Scheme 4). Oxidative coupling
of this substrate to form the ruthenacycle corresponding to
III likely does not occur due to steric constraints. In the case
of the trisubstituted allene carboxylic acid 37, the ruthena-
cycle corresponding to III does not undergo nucleophilic
capture. Elimination to the 1,3-diene product corresponding
to IV is not observed either, as such a process would involve
loss of a hindered proton and formation of a relatively
unstable methylene cyclohexane. Instead, a facile E2′ elimi-
nation leads to the 1,3-diene product 38.
Acknowledgment. We thank the National Science Foun-
dation and the National Institutes of Health, General Medical
Sciences Institute (GM 33049), for their generous support
of our programs. Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of Californias
San Francisco, supported by the NIH Division of Research
Resources.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0610136
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